ABSTRACT
Our study characterized the neurodevelopmental spectrum of individuals with PTEN Hamartoma Tumor Syndrome (PHTS), a syndrome that predisposes to both neurodevelopmental phenotypes and cancer risk. We aim to better understand life-impacting neurodevelopmental features of PHTS. Our study recruited 20 children/adolescents with PHTS, who were then administered assessments for autism spectrum disorder (ASD) and other neurocognitive measures, including assessment of IQ, executive and adaptive functioning, and health-related quality of life. Thirteen individuals (65%) were identified as having ASD, of which five were newly diagnosed during the study. Of those, ASD symptom severity was in the mild-moderate range for 77%. Overall, IQ was in the average range, with a mean of 92.61 (SD 24.45, p = 0.5), though there was a non-statistically significant trend toward individuals without ASD having a higher mean IQ (102.7 vs 82.3; p = 0.1). Subjects had significant impairment in processing speed (mean 75.38, SD 24.75, p < 0.05), decreased adaptive functioning skills across all domains, and a trend toward having more executive functioning problems. Individuals with PHTS are at increased risk of neurodevelopmental disorders, including ASD and impaired executive and adaptive functioning. Although clear guidelines exist for cancer surveillance for individuals with PHTS, additional guidelines and screening for neurodevelopmental disorders are warranted.
Subject(s)
Autism Spectrum Disorder , Hamartoma Syndrome, Multiple , PTEN Phosphohydrolase , Phenotype , Humans , Male , Female , Child , Adolescent , Hamartoma Syndrome, Multiple/genetics , Hamartoma Syndrome, Multiple/pathology , Hamartoma Syndrome, Multiple/diagnosis , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/pathology , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/diagnosis , PTEN Phosphohydrolase/genetics , Child, Preschool , Quality of LifeABSTRACT
Peutz-Jeghers syndrome (PJS) is a childhood-onset cancer predisposition syndrome that is associated with oral freckling and gastrointestinal polyposis. Male patients with PJS are at risk for large-cell calcifying Sertoli cell tumors in childhood. These tumors are estrogen-producing and can cause symptoms of precocious puberty, gynecomastia, and growth acceleration. Here we discuss our experience with spontaneous resolution or stabilization of breast enlargement without medical intervention in three patients with PJS and gynecomastia. These cases indicate that a watchful waiting approach can be considered in the management of gynecomastia in male children with PJS.
Subject(s)
Gynecomastia , Peutz-Jeghers Syndrome , Adolescent , Child , Child, Preschool , Humans , Male , Conservative Treatment , Gynecomastia/therapy , Gynecomastia/etiology , Peutz-Jeghers Syndrome/complications , Peutz-Jeghers Syndrome/therapy , Peutz-Jeghers Syndrome/pathology , Peutz-Jeghers Syndrome/geneticsABSTRACT
De novo mutations (DNMs) are increasingly recognized as rare disease causal factors. Identifying DNM carriers will allow researchers to study the likely distinct molecular mechanisms of DNMs. We developed Famdenovo to predict DNM status (DNM or familial mutation [FM]) of deleterious autosomal dominant germline mutations for any syndrome. We introduce Famdenovo.TP53 for Li-Fraumeni syndrome (LFS) and analyze 324 LFS family pedigrees from four US cohorts: a validation set of 186 pedigrees and a discovery set of 138 pedigrees. The concordance index for Famdenovo.TP53 prediction was 0.95 (95% CI: [0.92, 0.98]). Forty individuals (95% CI: [30, 50]) were predicted as DNM carriers, increasing the total number from 42 to 82. We compared clinical and biological features of FM versus DNM carriers: (1) cancer and mutation spectra along with parental ages were similarly distributed; (2) ascertainment criteria like early-onset breast cancer (age 20-35 yr) provides a condition for an unbiased estimate of the DNM rate: 48% (23 DNMs vs. 25 FMs); and (3) hotspot mutation R248W was not observed in DNMs, although it was as prevalent as hotspot mutation R248Q in FMs. Furthermore, we introduce Famdenovo.BRCA for hereditary breast and ovarian cancer syndrome and apply it to a small set of family data from the Cancer Genetics Network. In summary, we introduce a novel statistical approach to systematically evaluate deleterious DNMs in inherited cancer syndromes. Our approach may serve as a foundation for future studies evaluating how new deleterious mutations can be established in the germline, such as those in TP53.
Subject(s)
Breast Neoplasms/genetics , Genetic Predisposition to Disease/genetics , Germ-Line Mutation/genetics , Li-Fraumeni Syndrome/genetics , Ovarian Neoplasms/genetics , Adult , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/diagnosis , Family , Female , Humans , Pedigree , Tumor Suppressor Protein p53/genetics , Young AdultABSTRACT
INTRODUCTION: To assess the upper gastrointestinal (UGI) cancer risk and surveillance outcomes in Li-Fraumeni syndrome (LFS). METHODS: Analysis of the International Agency for Research on Cancer database and a single-center adult LFS cohort. RESULTS: UGI cancer was present in 7.2% of families and 3.9% of individuals with a pathogenic/likely pathogenic TP53 mutation in International Agency for Research on Cancer; 29% occurred before age 30. Our institutional cohort had 35 individuals (31% of the LFS cohort) with 48 cumulative upper endoscopies; 3 (8.5%) individuals had concerning UGI findings. DISCUSSION: UGI cancer is observed in LFS. Upper endoscopy should be part of a comprehensive LFS surveillance program.
Subject(s)
Esophageal Neoplasms/etiology , Germ-Line Mutation , Li-Fraumeni Syndrome/complications , Stomach Neoplasms/etiology , Tumor Suppressor Protein p53/genetics , Adolescent , Adult , Aged , Esophageal Neoplasms/genetics , Female , Genetic Predisposition to Disease , Humans , Li-Fraumeni Syndrome/genetics , Male , Middle Aged , Risk Factors , Stomach Neoplasms/genetics , Young AdultABSTRACT
PURPOSE: Women with Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome caused by germline mutations in TP53, have an over 50% risk of developing breast cancer by age 70. Patients with LFS are at risk for radiation-induced malignancies; however, only small case series have prior investigated radiation risks in the treatment of breast cancer. We therefore aimed to investigate the risk of malignancy in breast cancer patients with LFS following adjuvant radiotherapy. METHODS: A single-institution retrospective chart review was conducted for female breast cancer patients with confirmed germline TP53 mutation. The frequency of radiation-induced malignancies in LFS patients was compared to non-LFS breast cancer cases reported in the Penn Medicine Cancer Registry via statistical analyses. RESULTS: We identified 51 female LFS breast cancer patients with 74 primary diagnoses. Fifty-seven% had a history of breast cancer only, and 25% had breast cancer as their presenting diagnosis of LFS. LFS-associated breast cancers were predominantly invasive ductal carcinoma (48%) and HER2+ (58%). Twenty patients underwent adjuvant radiotherapy with a median follow-up of 12.5 (2-20) years. Of 18 patients who received radiation in a curative setting, one (6%) patient developed thyroid cancer, and one (6%) patient developed sarcoma in the radiation field. This risk for radiation-induced malignancy associated with LFS was higher for both sarcoma and thyroid cancer in comparison with the control cohort. CONCLUSIONS: We found a lower risk of radiation-induced secondary malignancies in LFS breast cancer patients than previously reported in the literature (33% risk of radiation-induced sarcoma). These findings suggest that LFS may not be an absolute contraindication for radiotherapy in breast cancer. The potential risk for locoregional recurrence without radiotherapy must be weighed against the long-term risk for radiation-induced malignancies in consideration of adjuvant radiotherapy for LFS breast cancer patients.
Subject(s)
Breast Neoplasms/radiotherapy , Carcinoma, Ductal, Breast/radiotherapy , Carcinoma, Lobular/radiotherapy , Li-Fraumeni Syndrome/complications , Neoplasm Recurrence, Local/radiotherapy , Neoplasms, Radiation-Induced/etiology , Radiotherapy, Adjuvant/adverse effects , Adolescent , Adult , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/pathology , Female , Follow-Up Studies , Germ-Line Mutation , Humans , Lymphatic Metastasis , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasms, Radiation-Induced/pathology , Prognosis , Retrospective Studies , Survival Rate , Tumor Suppressor Protein p53/genetics , Young AdultABSTRACT
Gastrointestinal polyps are mucosal overgrowths that, if unchecked, can undergo malignant transformation. Although relatively uncommon in the pediatric age group, they can be the harbingers of multiorgan cancer risk and require close management and follow-up. Additionally, as many polyposis syndromes are inherited, appropriate genetic testing and management of relatives is vital for the health of the entire family. In this review, we discuss both common and uncommon childhood gastrointestinal polyposis syndromes in terms of clinical presentation, management, and surveillance. We also detail any additional malignancy risk and surveillance required in the pediatric age group (<21 years old). Through this review, we provide a framework for gastroenterologists to manage the multifaceted nature of pediatric polyposis syndromes.
Subject(s)
Adenomatous Polyposis Coli/genetics , Gastrointestinal Neoplasms/genetics , Genetic Predisposition to Disease , Peutz-Jeghers Syndrome/genetics , Adolescent , Child , Genetic Counseling , Genetic Testing , Humans , Practice Guidelines as TopicABSTRACT
BACKGROUND: Advances in the application of genetic technologies reveal a growing number of heritable disorders associated with an increased risk to develop cancer during childhood. As genetic testing is increasingly employed in the clinical setting, it is essential to understand whether parents communicate with their children about test results and to elucidate the factors that influence the content and outcomes of these conversations. METHODS: Semistructured interviews were conducted with 14 parents whose children tested positive for Li-Fraumeni syndrome (LFS). Semantic content analysis was performed on transcribed interviews, focusing on questions related to parent-child conversations about the genetic testing process and disclosure of positive test results. RESULTS: All parents emphasized the importance of involving children in conversations about LFS. The majority (93%) identified as being part of "cancer families" in which prior experiences with cancer created opportunities for communication. While all had spoken with their children about cancer, only seven (50%) specifically disclosed to their children that they had tested positive for LFS. The most common reason cited for nondisclosure at the time of this study was the young age of the children. CONCLUSION: Parents of children with LFS desire open conversations about genetic testing and cancer risk. These conversations are challenging yet essential to enable child understanding of genetic risk status and enhance compliance with health-promoting and cancer surveillance measures. Development of age-appropriate educational materials and novel clinical models to facilitate parent-child conversations about genetic test results and risk status for cancer are needed.
Subject(s)
Communication , Li-Fraumeni Syndrome , Neoplasms/genetics , Parent-Child Relations , Truth Disclosure , Adolescent , Adult , Child , Child, Preschool , Female , Genetic Predisposition to Disease/psychology , Genetic Testing , Humans , Infant , Infant, Newborn , Li-Fraumeni Syndrome/complications , Li-Fraumeni Syndrome/diagnosis , Li-Fraumeni Syndrome/genetics , Male , Middle Aged , Young AdultABSTRACT
Children with Beckwith-Wiedemann Syndrome (BWS) and Isolated Hemihypertrophy (IHH) are at an increased risk for developing tumors. Tumor screening in this population is currently being reassessed by several groups and the effect on patients and patient-families has been argued both as a reason to screen and not to screen. Parental perspectives on this topic have never been systematically addressed for the BWS population. Here, we conducted a parent-based survey to evaluate knowledge and attitudes toward tumor screening in patients affected by BWS/IHH. A total of 261 surveys were completed. Overall, parents reported that screening decreased their worry and did not feel that screening increased worry or created a burden. This effect was observed across various demographic variables and other factors examined. Almost all significant differences observed could be attributed to parental knowledge of tumor risk. Parents who correctly identified their child's tumor risk were more likely to agree with stratified screening recommendations according to BWS type and risk, and were less likely to feel worried if recommendations were changed. These results highlight the need to educate families about their child's genetic type and tumor risk in order to facilitate an informed decision about tumor screening.
Subject(s)
Attitude to Health , Beckwith-Wiedemann Syndrome/diagnosis , Early Detection of Cancer/psychology , Mass Screening/psychology , Parents/psychology , Beckwith-Wiedemann Syndrome/psychology , Child , Cross-Sectional Studies , Early Detection of Cancer/statistics & numerical data , Female , Humans , Male , Mass Screening/statistics & numerical data , Parent-Child Relations , RegistriesABSTRACT
Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome that may present with a first cancer before or during adolescence/young adulthood. Families offered LFS genetic testing for their children can inform our understanding of how the unique developmental context of adolescence influences parental perspectives about genetic testing and discussions of cancer risk. In this study, semi-structured interviews were conducted with 46 parents of children at risk for LFS to capture those perspectives. Analysis utilized summary descriptive statistics and inductive qualitative content coding. Most parents (33/46; 72%) expressed beliefs that adolescence influences the importance of LFS testing and/or discussions about genetic risk. Twenty-six parents related this influence to cognitive, physical, and social changes occurring during adolescence. Aspects of adolescence perceived as promoting LFS testing/discussion included developmental appropriateness, risks of cancer in adolescence, need for medical screening decisions, influence on behaviors, transition to adult health care, and reproductive risks. Aspects of adolescence perceived as complicating LFS testing/discussions included potential negative emotional impact, misunderstanding, added burden, and negative impact on self-image or future planning. Parents recognize the complex influence that adolescence has on LFS testing and conversations surrounding results. Further research is needed to understand the actual impact of genetic testing on young people, and how to best support parents and adolescents within the broader context of heritable diseases.
Subject(s)
Hamartoma Syndrome, Multiple , Humans , Mosaicism , PTEN Phosphohydrolase/genetics , PhenotypeSubject(s)
Hamartoma Syndrome, Multiple , Hemangiosarcoma , Neuroblastoma , Skin Neoplasms , Child , Hamartoma Syndrome, Multiple/complications , Hamartoma Syndrome, Multiple/genetics , Hamartoma Syndrome, Multiple/pathology , Humans , Neuroblastoma/genetics , PTEN Phosphohydrolase/genetics , Skin Neoplasms/geneticsABSTRACT
Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth and cancer predisposition syndrome, associated with both benign and malignant adrenal findings. Literature review and an institutional case series elucidate the wide spectrum of adrenal findings in BWS patients. The altered expression of the 11p15 region is likely related to adrenal gland hyperplasia and growth dysregulation. Given the absence of guidelines for managing adrenal findings in BWS, we propose a systematic approach to adrenal findings in BWS patients, to allow for maximum detection of potentially malignant pathology without posing additional risk to patients.
Subject(s)
Adrenal Gland Diseases/diagnosis , Adrenal Gland Diseases/etiology , Adrenal Gland Diseases/therapy , Beckwith-Wiedemann Syndrome/complications , HumansABSTRACT
Whether children should be offered genetic testing for cancer risk is much debated but young voices are rarely heard in these conversations. The current study explored perspectives of genetic testing held by adolescents and emerging adults in families with Li Fraumeni syndrome (LFS). Twelve 12- to 25-year-olds in families with LFS completed qualitative interviews for this study. All believed that testing should be offered for children but many qualified this statement saying parental approval would be needed and testing should be optional. Genetic testing was seen as way to learn of risk status, allow for disease prevention efforts, and reduce uncertainty and anxiety. Perceived disadvantages included negative emotions associated with the testing result. Participants generally felt that children should be involved in the testing decision, but that parents could unilaterally decide to have a child tested in certain circumstances (e.g., young age, high risk). All who were aware of having been tested and of their test result (n = 7; 4 positive) said testing had no negative impact on their outlook and they agreed with the decision to undergo testing. Implications of these findings for clinical practice and future research are discussed.
Subject(s)
Genetic Predisposition to Disease , Genetic Testing , Germ-Line Mutation/genetics , Li-Fraumeni Syndrome/genetics , Adolescent , Adult , Child , Female , Humans , Male , Parent-Child Relations , Young AdultABSTRACT
BACKGROUND: Li-Fraumeni syndrome is a rare genetic cancer predisposition syndrome caused by germline TP53 mutations. Up to 20% of mutation carriers develop cancer during childhood. The benefits of TP53 mutation testing of children are a matter of debate and knowledge of parent decision-making around such testing is limited. The current study examined how parents make decisions regarding TP53 testing for their children. METHODS: Families offered and those pursuing TP53 testing for their children were identified across the study sites. Qualitative interviews with 46 parents (39 families) were analyzed to describe decision-making styles and perceived advantages and disadvantages of testing. RESULTS: TP53 mutation testing uptake was high (92%). Three decision-making styles emerged. Automatic decisions (44% of decisions) involved little thought and identified immediate benefit(s) in testing (100% pursued testing). Considered decisions (49%) weighed the risks and benefits but were made easily (77% pursued testing). Deliberated decisions (6%) were difficult and focused on psychosocial concerns (25% pursued testing). Perceived advantages of testing included promoting child health, satisfying a "need to know," understanding why cancer(s) occurred, suggesting family member risk, and benefiting research. Disadvantages included psychosocial risks and privacy/discrimination/insurance issues. CONCLUSIONS: Although empirical evidence regarding the benefits and risks of TP53 testing during childhood are lacking, the majority of parents in the current study decided easily in favor of testing and perceived a range of advantages. The authors conclude that in the context of a clinical diagnosis of Li-Fraumeni syndrome, parents should continue to be offered TP53 testing for their children, counseled regarding potential risks and benefits, and supported in their decision-making process.
Subject(s)
Decision Making , Genetic Testing , Germ-Line Mutation , Heterozygote , Li-Fraumeni Syndrome/genetics , Parents , Tumor Suppressor Protein p53/genetics , Adolescent , Adult , Child , Child, Preschool , Female , Genetic Counseling , Genetic Predisposition to Disease , Health Behavior , Humans , Infant , Interviews as Topic , Male , Middle Aged , Qualitative ResearchSubject(s)
Colorectal Neoplasms/diagnosis , Early Detection of Cancer/methods , Li-Fraumeni Syndrome/diagnosis , Adolescent , Adult , Age of Onset , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Databases, Factual , Genetic Predisposition to Disease , Humans , Incidence , Li-Fraumeni Syndrome/epidemiology , Li-Fraumeni Syndrome/genetics , Male , Middle Aged , Mutation , Phenotype , Philadelphia/epidemiology , Predictive Value of Tests , Retrospective Studies , Risk Factors , Time Factors , Tumor Suppressor Protein p53/genetics , Young AdultABSTRACT
9q22.3 microdeletion syndrome is a well-described contiguous deletion syndrome with features of Gorlin syndrome and other manifestations. Commonly reported findings in addition to those of Gorlin syndrome include metopic craniosynostosis, hydrocephalus, intellectual disability, and minor facial anomalies. The critical region for this condition was found to include the PTCH1 and FANCC genes; however, other genes are often deleted in affected individuals but their role in the observed phenotype is not understood. Fewer than 50 individuals with 9q22.3 microdeletion have been reported, all diagnosed postnatally on the basis of the phenotype. A confirmed prenatal diagnosis and accompanying fetal imaging has not been reported to date. We describe a patient with prenatally diagnosed 9q22.3 microdeletion syndrome following the ultrasonographic identification of trigonocephaly, macrosomia, organomegaly, ventriculomegaly, and anomalous vertebrae.
Subject(s)
Abnormalities, Multiple/diagnostic imaging , Chromosome Deletion , Craniosynostoses/diagnostic imaging , Hydrocephalus/diagnostic imaging , Polyhydramnios/diagnostic imaging , Abnormalities, Multiple/genetics , Chromosome Disorders/diagnostic imaging , Chromosome Disorders/genetics , Chromosomes, Human, Pair 9/genetics , Craniosynostoses/genetics , Female , Humans , Hydrocephalus/genetics , Infant , Polyhydramnios/genetics , Polymorphism, Single Nucleotide , Pregnancy , Ultrasonography, PrenatalABSTRACT
OBJECTIVE: Children with cancer-predisposing conditions are at increased risk to develop and die of cancer. Limited data exist on the utility of whole-body MRI as a cancer screening tool in children. In this study, we examined the diagnostic performance of whole-body MRI as a mechanism of tumor surveillance for children at increased genetic risk for cancer. MATERIALS AND METHODS: Twenty-four children (six boys and 18 girls) with a mean age of 11.2 years (range, 2.1-18.2 years) underwent 50 unenhanced whole-body MRI examinations over a 5-year period. Scans were retrospectively reviewed and assessed for image quality; sequences performed; and the presence of osseous, soft-tissue, or solid organ abnormalities. Findings suggestive of a malignancy were stratified by risk as low (< 20% chance for cancer), moderate (20-80%), or high (> 80%). MRI findings were correlated with medical records, biopsy results, or additional follow-up imaging; biopsy and follow-up were considered as the reference standards. RESULTS: Forty-eight of 50 (96%) examinations were of very good quality. Nine findings suspicious for malignancy were identified, including two high-risk, two moderate-risk, and five low-risk lesions. One high-risk lesion was proven by biopsy to be a papillary thyroid carcinoma, with the remaining lesions deemed nonmalignant. The sensitivity of whole-body MRI was 100%; specificity, 94%; positive predictive value, 25%; and negative predictive value (NPV), 100%. CONCLUSION: Unenhanced whole-body MRI is safe and produces excellent images. The high sensitivity, specificity, and NPV make whole-body MRI a valuable cancer screening tool in children with a genetic predisposition for cancer.
Subject(s)
Early Detection of Cancer , Genetic Predisposition to Disease , Magnetic Resonance Imaging/methods , Neoplastic Syndromes, Hereditary/diagnosis , Whole Body Imaging , Adolescent , Biopsy , Child , Child, Preschool , Female , Humans , Male , Predictive Value of Tests , Retrospective Studies , Sensitivity and SpecificityABSTRACT
In July 2023, the American Association for Cancer Research held the second Childhood Cancer Predisposition Workshop at which international experts in pediatric cancer predisposition met to update the previously published 2017 consensus statements on pediatric cancer predisposition syndromes. Since 2017, advances in tumor and germline genetic testing and increased understanding of cancer predisposition in pediatric cancer patients have led to significant changes in clinical care. Here, we provide an updated genetic counseling framework for pediatric oncology professionals. The framework includes: (1) referral indications and timing; (2) somatic and germline genetic testing options; (3) testing for adult-onset cancer predisposition syndromes in children with and without cancer; (4) evolving genetic counseling models to meet the increased demand for genetic testing; (5) barriers to cancer genetic testing and surveillance in children; and (6) psychosocial and equity considerations regarding cancer genetic testing and surveillance in children. Adaptable genetic counseling services are needed to provide support to pediatric oncology provider teams and diverse patients with pediatric cancer, cancer predisposition, and their families.
ABSTRACT
With the increasing use of comprehensive germline genetic testing of children and adolescents with cancer, it has become evident that pathogenic variants (PV) in adult-onset cancer predisposition genes (aoCPG) underlying adult-onset cancer predisposition syndromes, such as Lynch syndrome or hereditary breast and ovarian cancer, are enriched and reported in 1% to 2% of children and adolescents with cancer. However, the causal relationship between PVs in aoCPGs and childhood cancer is still under investigation. The best-studied examples include heterozygous PVs in mismatch repair genes associated with Lynch syndrome in children with mismatch repair deficient high-grade glioma, heterozygous PVs in BARD1 in childhood neuroblastoma, and heterozygous PVs in BRCA2 in children with rhabdomyosarcoma. The low penetrance for pediatric cancers is considered to result from a combination of the low baseline risk of cancer in childhood and the report of only a modest relative risk of disease in childhood. Therefore, we do not advise that healthy children empirically be tested for PVs in an aoCPG before adulthood outside a research study. However, germline panel testing is increasingly being performed in children and adolescents with cancer, and exome and genome sequencing may be offered more commonly in this population in the future. The precise pediatric cancer risks and spectra associated with PVs in aoCPGs, underlying cellular mechanisms and somatic mutational signatures, as well as treatment response, second neoplasm risks, and psycho-oncological aspects require further research.
Subject(s)
Genetic Predisposition to Disease , Genetic Testing , Germ-Line Mutation , Adolescent , Adult , Child , Female , Humans , Age of Onset , Genetic Testing/methods , Neoplasms/genetics , Neoplasms/diagnosis , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/diagnosisABSTRACT
Inherited bone marrow failure syndromes (IBMFS) are a group of heterogeneous disorders that account for â¼30% of pediatric cases of bone marrow failure and are often associated with developmental abnormalities and cancer predisposition. This article reports the laboratory validation and clinical utility of a large-scale, custom-designed next-generation sequencing panel, Children's Hospital of Philadelphia (CHOP) IBMFS panel, for the diagnosis of IBMFS in a cohort of pediatric patients. This panel demonstrated excellent analytic accuracy, with 100% sensitivity, ≥99.99% specificity, and 100% reproducibility on validation samples. In 269 patients with suspected IBMFS, this next-generation sequencing panel was used for identifying single-nucleotide variants, small insertions/deletions, and copy number variations in mosaic or nonmosaic status. Sixty-one pathogenic/likely pathogenic variants (54 single-nucleotide variants/insertions/deletions and 7 copy number variations) and 24 hypomorphic variants were identified, resulting in the molecular diagnosis of IBMFS in 21 cases (7.8%) and exclusion of IBMFS with a diagnosis of a blood disorder in 10 cases (3.7%). Secondary findings, including evidence of early hematologic malignancies and other hereditary cancer-predisposition syndromes, were observed in 9 cases (3.3%). The CHOP IBMFS panel was highly sensitive and specific, with a significant increase in the diagnostic yield of IBMFS. These findings suggest that next-generation sequencing-based panel testing should be a part of routine diagnostics in patients with suspected IBMFS.